In current oncology clinical practice, the histological type and stage of cancer are central determinants of prognosis and treatment decisions. Recently, there has been acceleration in application of molecular predictors to guide clinical decision making with an ultimate goal of individualizing cancer care. However, these molecular predictors have largely been limited to the most common cancers and a few less common cancers that have a well-defined molecular pathogenesis. Yet, uncommon cancers as a group account for about 25% of all malignancies. In this proposal, we propose to complement our ongoing genetic analysis of familial chordoma, a rare cancer thought to arise from notochord, with approaches being applied to individualization of common cancers. The overall goal is to both advance the understanding of pathogenesis of chordoma and guide therapeutic decision making. The successful understanding of the biology of chordoma may provide a roadmap for the study of other rare cancers using analogous approaches and extend individualized cancer care to a broader array of patients. Specific Aim 1. Identify the familial chordoma gene(s). Hypothesis: mutation of a familial chordoma gene(s) predisposes individuals in these families to develop chordoma. Using families with multiple individuals affected with chordoma, my laboratory will identify the familial chordoma gene(s) through sequence analysis and aCGH identification of all genetic variants in the linked region of the largest family. This gene and biochemically-related genes will then be examined in smaller families. Specific Aim 2. Determine the role of brachyury in chordoma cell growth and survival. Hypothesis: brachyury promotes chordoma cell growth and survival, and is a key mediator of chordoma tumorigenesis. Brachyury is a transcription factor that plays a critical role in notochord maintenance, is induced by wnt/beta-catenin signaling, is expressed at high levels in chordoma, and is within the minimal disease gene region for familial chordoma. We will knock-down brachyury in chordoma cells and force its expression in non-chordoma cells followed by assessment of characteristics associated with the malignant phenotype. Specific aim 3. Identify mitogenic pathways altered in chordoma. Hypothesis: Unregulated growth in chordoma is due to dysregulation of specific transcriptional/mitogenic signaling pathways. Leveraging the sensitivity to specific pharmacologic agents, we will dissect growth regulatory signaling pathways in chordoma cells. Based upon growth inhibitory activity in vitro against a chordoma line to the proteosome inhibitor, bortezomib, we will initial focus on defining the transcriptional and signaling pathways altered by this agent. Potential Impact on Veterans Health Care: Although chordoma is a rare tumor, the results of this work will be highly relevant for cancers commonly noted in the Veterans Affairs health care system through better understanding of pathogenesis of malignancy that may establish the basis for improved clinical care. PUBLIC HEALTH RELEVANCE: Cancer is a leading cause of death and suffering. Essentially all human cancers have inherited and/or acquired changes in the genes of cancer cells. Characterizing the changes in genes of cancer cells has been instrumental in recent advances in the clinical care of patients with cancer including improved diagnosis, refinement of prognosis, design of novel therapeutic strategies, and monitoring response to therapy. The identification and characterization of the familial chordoma gene and acquired mutations associated with sporadic (non-familial) chordomas has the potential to increase our understanding of cause(s) of common malignancies.